Certain chromium compounds are well-established human respiratory toxins and carcinogens. Major environmental health concerns stem from the deposition of chromium in industrial waste either in the form of dissolved chromate compounds released to surface waters or chromate slag used in landfills. Chromium is generated as an atmospheric pollutant during ferrochrome production, ore refining, welding, and incinerations of all types. Hexavalent chromate, Cr(VI), is currently one of 33 compounds listed by the Environmental Protection Agency (EPA) to pose the greatest potential health threat in urban areas and chromate compounds are listed by NIOSH (National Institute of Occupational Safety and Health) to be one of the major causes of occupational lung cancer. While considerable information exists regarding Cr(VI) genotoxicity in cell culture, the mechanisms by which Cr(VI) causes lung injury and carcinogenesis in vivo are still unknown. A major drawback has been the lack of a suitable animal model that reproduces the lung tissue microenvironment induced by chromium exposure in humans. One critical question is why Cr(VI), shown to be one of the most potent genotoxic agents in occupational and environmental settings, fails to induce carcinogenesis in experimental animals except in very select cases. We propose that most animal models fail to induce tumor development in response to inhaled Cr(VI) because they are missing a key contributing factor: the appropriate type of chronic tissue inflammation. Thus, the goal of our proposed studies is to directly test the contribution of inflammatory processes to chromate-mediated lung cancer development, using a new mouse model of Cr(VI) respiratory exposure that includes chronic lung tissue inflammatory responses. For our proposed studies we will use the BALB/c mouse model for intranasal delivery of hexavalent basic zinc chromate (ZnCrO44Zn(OH)2), which is an intermediately water soluble chromate typically encountered in mining and chromate production facilities and is also present as an environmental atmospheric contaminant in urban areas surrounding ferrochrome production facilities. The following two working hypotheses will be tested: 1) Cr(VI)-mediated oncogenesis is associated with sequential changes in tissue inflammation, injury/repair and cell survival dysregulation;2) Inflammatory processes are required for the neoplastic events that lead to lung tumor generation by Cr(VI) exposure. Our long-term goal is to establish a non-human model of Cr(VI) exposure that can be used to dissect the mechanism whereby inhaled Cr(VI) induces lung cancer. Results from these studies will have the added benefit of identifying molecular targets for potential interventional or preventive therapy. An important aspect of the significance of the proposed studies is the use of an occupationally and environmentally relevant form of particulate Cr(VI), as a pure compound, with a delivery system which mimics human exposure. The findings will also be relevant to other lung particulates that induce injury and cancer. PUBLIC HEALTH RELEVANCE: Certain particulate chromium compounds are well established atmospheric pollutants and human respiratory toxins and carcinogens, while environmental and occupational exposure to chromate continues to loom large as a major public health issue. This proposal will employ a new mouse model that reproduces the lung tissue microenvironment induced by chromium exposure in humans. The proposed studies will provide valuable new insights into the complex etiology of the disease process, as well as provide a means to evaluate the contribution of the inflammatory environment and survival signaling pathways to chromium carcinogenesis.